Treatment Strategies in Marginal Zone

Lymphoma

Franco Cavalli M.D., F.R.C.P.

Scientific Director, Oncology Institute of Southern Switzerland (IOSI)

LyFE Programme

29-31 January 2016

Bellinzona, Switzerland

WHO Classification

Marginal Zone B-Cell Lymphomas

Not the same:Splenic Marginal Zone Lymphoma ~ 1% of all NHLs

Nodal Marginal Zone Lymphoma ~ 2% of all NHLs

Extranodal Marginal Zone Lymphoma of mucosa-associated lymphoid-tissue (MALT Lymphoma)

~ 8% of all NHLs

Marginal zone lymphomas in the SEER database

SEER program collects cancer incidence, treatment, and survival information from 18 areas in the United States, representing 28% of the population

Total 15,908 patients diagnosed between 1995 and 2009median age of 68 years

Incidence rate MALT lymphoma 1.59 per 100000 adults NMZL NMZL 0.83 per 100000SMZL 0.25 per 100000

MALT lymphomas 5%NMZL 2.4% SMZL 0.7% of all B-cell lymphoma

Array-CGH identifies both common or subtype-specific aberrations in MZL

• MZLs share 3q and 18q gains

• NMZL are more similar to EMZL than SMZL

• Extracopies of chr 3 and 18 are the same as in DLBCL

EMZL and SMZL profiles show differences

3p, 6p and 18p gains in EMZL

6q losses in EMZL (A20/TNFAIP3)

7q, 8p, 14q and 17p losses in SMZL

A. Rinaldi et al. Blood 117:1595-1604, 2011

Auto-antigens- Thyroid Hashimoto thyroiditis

- Salivary gland Myoepithelial sialoadenitis +/ - Sjögren S.

- Lung Lymphoid interstitial pneumopathy

MZL: associated with a chronic antigenic stimulation

MALT Lymphomas

Site Infectious agents

- Stomac Helicobacter pylori

- Intestin Campylobacter jéjuni

- Ocular adnexa Chlamydia psittaci

- skin Borrelia burgdorferi

Hepatite C Virus

Microbial pathogens

1.

2.

+

Splenic Nodal

MCLCCND1 +

SLL/CLL

Borderline

cases

CCDN1 -

Lplasmocytic L./

Waldenström

Hairy cell leukemia

(/ variant)

• Splenic

• MALT

• Nodal

- Villous L.

- / HCV

Splenic Red

pulp L with VL

Marginal Zone Lymphomas= derived from a memory B-cell? From a cell of the Marginal Zone

No discriminant marker !

MZL

Immunophenotype Cytogenetic Next generation sequencing (NGS)

MZL

CD20+ CD19+ CD79a+

CD5- CD23- CD10-CD43v

BCL2+

Matutes Score < 3

Splenic MZL

NOTCH2

30%

LPL/Waldenström CD22+f CD25+ CD103-del6q

+4 +3 +18

MYD88 L265P

90%

Hairy cell leukemiaCD103 CD11c CD25 (HC-2/) CD123 (=IL-3R)

Score RMN 3 ou 4 / 4

5q13 +5 del(5)

del(7)(q32) del(17)(q25)

t(11;20) t(2;8)

BRAF V600E 100%Absent in HCL-V and HCL

IGHV4-34

LLC/ SLL

CD20+

CD5+ CD23+ CD43+

CD10- FMC7- CD79b-

Matutes Score 4 ou 5 / 5

13q(del) 60%

+12 15-20%

11q (del) 30%

17pdel 2-30%

-

Swerdlow SH. et al. IARC 2008; Kiel et al. 2012; Rossi D et al. 2012; Tiacci E et al. 2011; Treon SP. et al.

7q (del) 45% +3/+3q

MALT L. : t(11;18), t(14;18),

t(1;14), t(3;14)

Diagnosis of MALT lymphoma(Extranodal Marginal Zone B-Cell Lymphoma of MALT)

HISTOLOGICAL FEATURES

centrocyte-like cells (usually) lymphoepithelial lesions plasma cell differentiation scattered transformed blasts admixed reactive T-cell follicular colonisation

IMMUNOPHENOTYPE

CD5, CD10, CD23, cyclin-D1, IgD negative CD20, CD21, CD35, IgM positive IRTA1 positive

Isaacson et al. in WHO Classification of Tumours of Haematopoietic &Lymphoid Tissues. IARC, Lyon 2008; pp. 214-7

Bacterial infections and other MALT lymphomas

Analogous to H. pylori the in the stomach:

Borrelia burgdorferi infection, may represent the background for the

development of cutaneous marginal zone B-cell lymphoma(Cerroni L. J Cutan Pathol 1997,

Roggero E. Hum Pathol 2000)

Chlamydophyla psittaci infection can provide the antigen stimulation, which

may contribute to the pathogenesis of ocular adnexa lymphomas(Ferreri A. J Natl Cancer Inst 2004)

Campylobacter jejuni may be associated with IPSID

(Lecuit M. N Engl J Med 2004)

Achromobacter xylodoxidans possibly related to BALT-lymphoma

(Sammassimo S. ASH 2011,Adam P. Br. J. Haematol 2013)

H. pylori translocates the bacterial protein CagA into gastric epithelial cells, and into MALT lymphoma B cells

CagA protein in gastric epithelialcells (where it deregulates

intracellular signaling pathways) and the tumor

B-cells within the gastric mucosa

CagA undergoes tyrosinephosphorylation in tumor B-

cellsand binds to intracellular SH-2

During persistent H. pylori infection CagA may act as an oncoprotein in B cells :

- activates extracellular signal-regulated kinase and p38 mitogen-activated PK

- upregulates the expressions of Bcl-2 and Bcl-XL, which prevents apoptosis

Wei-Cheng et al. Cancer Res 2010

H. pylori and MALT lymphoma: a model oftumor progression

BB B

B

BBB

B

BB B T

T

strain-specific

stimulation

mucosal T-cell proliferation

H. pylori-dependent

MALT lymphoma

B-cell proliferation

contact-dependent

B-cell stimulation

neutrophils activations with release of

genotoxicfree radicals

antigen selection

autoimmunity

genetic

alterations

T

additional geneticdamages

B

T

T

DLBCL

BB

BH. pylori chronic gastritis

H. pylori-independentMALT lymphoma

B

B

Ferrucci & Zucca, BJH 2007

BCL10 and MALT1translocations

CagA+

strains

lymphoma progression

antibiotic-resistant gastric lymphoma

raret(1;14)BCL10

deregulation

common t(11;18)

API2/MALT1

fusion

at non-GI sitest(14;18)MALT 1

deregulation

NF-kB

activation

Different chromosomal translocations affecting the same signalling pathway in MALT lymphoma

more recentlydescribed

t(3;14) FOXP1

overexpression

poorer outcome

and higher risk

of histological

transformation

?

Wild-type MALT 1 synergizes with BCL 10 to activate NF-B

<5% ~35% ~15%

A20 (TNFAIP3)

a negative regulator of

BCL10-mediatedNF-kB activation

deleted or mutated

in up to 40%

~10% ?

Controversial issues in the management of MALT lymphoma

staging procedures

who does not need antibiotics?

evaluation of responses

follow up policies

treatment of H. pylori-negative and non-gastric cases

second line treatments

Management of MALT lymphomarecent attempts to overcome the controversies

EGILS Consensus Report on gastric MALT lymphom(Ruskone Formestraux et al. Gut 2011; 60:747)

ESMO Guidelines Consensus Conference at 11-ICML, Lugano, June 2011(Dreyling et al. Ann Oncol 2012, in press)

Recommended procedures in gastric MALT lymphoma

EGD with multiple biopsies

histochemical examination for H. pyloriand serology studies if histology is negative

endoscopic ultrasound to evaluate the regional lymph nodes and gastric wall infiltration.

optional: FISH for the t(11;18) translocation

EGILS Consensus Report

ESMO Guidelines Consensus Conference

MALT lymphoma initial staging

multifocal disease in ≥25% of cases

variable FDG-avidity(but likely high in non-gastriclesions)

Zucca et al, Blood 2003

Thieblemont et al , Blood 2000

Raderer et al, JCO 2006

de Boer et al. Haematologica 2008

Papaxoinis et al , Ann Oncol 2008

Sretenovic et al, Eur J Haematol. 2009

Other site-specific staging procedures

Small Intestine (IPSID): Campylobacter Jejuni studies

Large intestine: colonoscopy

Lung: bronchoscopy + bronchoalveolar lavage

Salivary glands: ENT examination and ultrasound; Sjögrensyndrome studies (anti-SSA or anti-SSB)

Thyroid: ultrasound and thyroid function tests

Ocular adnexa: MRI (or CT scan) and ophthalmologic examination; C. psittaci studies may be considered

Breast: mammography and MRI (or CT scan)

Skin: Borrelia Burgdorferi studies may be considered (in endemic areas)

ESMO Guidelines Consensus Conference, Lugano 2011

HP eradication is the standard initial treatment for localized disease

EGILS ConsensusReport

HP eradication is the standard initialtreatment for localized disease

H. pylori eradication therapy must be given to allgastric MALT lymphomas, independently of stage

HP-negative patients with gastric MALT lymphomamay also receive anti-H pylori treatment.

Responses may require up to 12 months or more

Lymphomas with t(11;18) and those with lymphnode involvement are unlikely to regress after HPeradication

EGILS Consensus Report

Reference n staging CR rate time to CR relapses

procedure (%) (mos.) (n)

Savio, 1996 12 CT+EGD 84 2-4 0

Pinotti, 1997 45 CT+EGD 67 3-18 2

Neubauer, 1997 50 CT±EUS 80 1-9 5

Nobre Leitao, 1998 17 CT+EUS 100 1-12 1

Steinbach,1999 23 CT±EUS 56 3-45 0

Montalban, 2001 19 CT±EUS 95 2-19 0

Ruskone-Formestraux, 2001 24 CT+EUS 79 2-18 2

Bertoni, 2002 200 CT+EGD 62 3-24 15

Most gastric MALT lymphomas regressafter H. pylori eradication

Different definitions of lymphoma remission in different trials !

Score Description Histologic Features

CR Complete Remission Normal or empty LP and/or fibrosiswith absent or scattered plasma cells and lymphoid cells in the LP; no LEL

pMRD Probable Minimal Empty LP and/or fibrosis with aggregatesResidual Disease of lymphoid cells or lymphoid nodules in

the LP/MM and/or SM; no LEL

rRD Responding Focal empty LP and/or fibrosis; dense, Residual Disease diffuse or nodular lymphoid infiltrate,

extending around glands in the LP. FocalLEL or absent

NC No Change Dense, diffuse or nodular lymphoidinfiltrate with LEL (LEL „„may be absent‟‟)

GELA score for lymphoma response evaluation after H pylori eradication

Copie-Bergman et al, Gut 2003; Copie-Bergman et al, Br J Haematol 2012

LP=lamina propria; LEL= lymphoepithelial lesions; MM=muscularis mucosa; SM=submucosa

LY03 trial of gastric MALT lymphoma

B. Hancock, et al. Br J Haematol, 2009

chlorambucil vs. observationafter anti-Helicobacter therapy

Long-term outcome after H. pylori eradication(IOSI and Varese series)

A. Stathis et al. Ann Oncol , 2009

N=105, stage IE

f-up, 76 mos

Remission rate, 76%

Long-term clinical control in most cases:

43% of responders had histological score fluctuations

57% had stable MRD

5-year OS is 92%.

Long-term outcome after H. pylorieradication (Japan GAST study group)

Nakamura S. Gut 2012

Long-term surveys after H. pylorieradication

Wundisch et al. JCO, 2005

Fischbach et al. Gut, 2007

Stathis et al. Ann Oncol , 2009

Nakamura et al. Gut 2012

not only patients with molecular residual disease may remain stable but also those with minimal histological MALT lymphoma residuals

A watch and wait policy seems safe in patients with minimal hRD or histological-only local relapse

How long to follow up after antibiotics?

Life-long?

Patients with gastric MALT lymphoma have a 6 times higher risk for gastric adenocarcinoma in comparison with the general population and the risk is highest in patients younger than 60

Capelle et al . Eur J Cancer, 2008

PFS according to C. psittacieradication (IELSG-27 study)

Successful eradication may affect PFS

No MZL relapses among 6 CRs

PRs successfully managed with “watch & wait” (median TTP: 24+ months)

at a median f-up of 37 mos, 94% are alive (2 unrelated deaths)

Ferreri AJM et al. J Clin Oncol 2012

27

Antibiotic therapy in non-Gi MALT Lymphoma - A review

Only scattered reports besidesOAML, in which antibiotic theralyusing doxycycline appears a reasonable first-line treatment

B. Kiesewetter and R. Raderer. Blood 2013; 122:1350-1357

Radiotherapy in gastric MALT lymphoma

Author n RT dose (Gy) FFP

Schechter, 1998 17 28-43 100% at 2 yrTsang, 2001 9 20-30 100% at 5 yrYahalom, 2002 51 30 median 89% at 4 yrHitchcock, 2002 9 34 median 78% (100% local)

• optimal RT volume, dose and technique? • does this really translate to cure?• in a very indolent condition, is the potential toxicity acceptable?• long term safety? (malignancy, gastric and renal toxicity)

RT Toxicity can be reducedusing modern 3D techniques and minimizing the RT dose to the kidneys and the liver

excellent local control in non-gastric sites , too!

Long-term outcome for gastric MALT lymphoma with radiotherapy: a retrospective multi-centre IELSG study

Wirth A et al. Ann Oncol 2013

Freedom from failure measured from date of commencement of radiotherapy

Chemotherapy in MALT lymphoma

Only one randomised trial (Zucca et al, 2010)

Single alkylating agents: 100% ORR (75%CR) (Hammel 1995)

Cladribine: 100% ORR (84% CR); higher CR rate in gastricthan extragastric (important hematologic toxicity grade andincreased risk of secondary MDS) (Jaeger 2002 and 2006)

Chlorambucil plus Mitoxantrone and Prednisone as well as Fludarabine in combination with Mitoxantrone and the classic CVP are active and well-tolerated regimens (Wohrer 2003; Zinzani

2004)

Aggressive anthracycline-containing regimens to be reserved for cases with transformation or bulky masses (Thieblemont 2005)

Bendamustine combinations currently under investigation

response n %

ORR 25 73

SD 6 18

PD 3 9

Rituximab activity in MALT lymphoma

IELSG phase II study, Conconi et al. Blood 2003

34 pts, 11 with prior chemotherapy,15 gastric, 20 stage IV

Marginal zone lymphomas

International Extranodal Lymphoma Study Group - IELSG 19 Randomised Study

E. Zucca, 12-ICML, Hematol Oncol 2013. 31(suppl 1):97. Abs 007

Response

ORR 110 (85%) 124 (95%) 104 (79%)

CR* 80 (62%) 104 (80%) 73 (55%)

PR 30 (23%) 20 (15%) 31 (23%)

SD 11 (8%) 1 (<1%) 15 (11%)

PD 7 (5%) 4 (3%) 9 (7%)

NA 2 (1.5%) 2 (1.5%) 4 (3%)

* R-Chl vs. Chl, P=0.001 R-Chl vs. R,

P<0.001; Chl vs. R, P= 0.372

Response to Treatment

International Extranodal Lymphoma Study Group - IELSG 19 Randomised Study

E. Zucca, 12-ICML, Hematol Oncol 2013. 31(suppl 1):97. Abs 007

Event-Free Survival

5-year EFS (95%CI):Chlorambucil , 52% (42%-60%)R-Chlorambucil, 70% (61%-77%)Rituximab, 51% (40%-61%)

Log-rank HR 95% C.I.R vs. Chl, P=0.957 0.99 (0.82-1.20)R-Chl vs. Chl, P=0.0005 0.52 (0.35-0.75)R-Chl vs. R, P= 0.0015 0.51 (0.33-0.78)

International Extranodal Lymphoma Study Group - IELSG 19 Randomised Study

E. Zucca, 12-ICML, Hematol Oncol 2013. 31(suppl 1):97. Abs 007

A. Salar, 12-ICML, Hematol Oncol 2013. 31(suppl 1):129-130. Abs 100

R-Bendamustine as First Line Treatment

for MALT Lymphoma

Treatment of patients who failed antibiotics and nongastric cases

Involved-field radiotherapy: 30 to 40 Gy in 15-20 fractions using modern radiation techniques

Chemotherapy and/or immunotherapy:

Chemotherapy and Rituximab are effective in patients with MALT lymphoma of all stages

Both radiotherapy and chemotherapy have a curative potential

There is no definitive evidence in favour of one of these two modalities

Surgery restricted to the treatment of complications

If clinical trials are available, patients should be included

EGILS Consensus ReportESMO Guidelines Consensus Conference

Ph-II MALT Lymphoma

ORR Study

Everolimus 20% IELSG

Bortezomib 48% IELSG

Lenalidomide 61% Vienna

R-Lenalidomide 89% Mayo

Histology transformation (HT) in MZLs

Franceschetti S. ASH 2012

the risk of HT is low across all MZL types (3 - 4%)

the incidence of HT in MZL is lower than that of other indolent B cell malignancies

as also observed in FL and CLL, HT in MZL occurs relatively early during the clinical course, pointing to putative biological differences at diagnosis in MZL patients destined to transform

MZL Survival: analysis of the SEER database

Survival in MALT lymphomas according to site

Nodal MZL

MALT lymphoma

Olszewski AJ et al. Cancer 2013

Overall survival

gastrointestinal and pulmonary sites 5-yrs LRDs 9.5%-14.3%ocular, cutaneous, endocrine sites 5-yrs LRDs 4.5%-7.8% (P<.0001)

MZL Survival: analysis of the SEER database

Outcome improvement over the time

Cumulative incidence of lymphoma related deaths

Nodal MZL

MALT lymphoma

Olszewski AJ et al. Cancer 2013

Outcome improvement…

Splenic Marginal Zone lymphoma

Diagnosis

Mandatory

Full blood count and Blood cytology

Blood Flow cytometry : CD5−, CD10−, CD19+, CD23−

CD27+, CD43−, FMC7±, kappa / lambda

Optional

Caryotype / FISH CCND1

IgVH Mutated 2/3 - Biased usage VH1.2, VH1–2, VH3–23, VH4–34

In the future : BRAF mutation 0% - MYD88 : 0% - NOTCH2 : 30%

The diagnosis of SMZL at present does not strictly require a splenectomy

Matutes E et al. Leukemia 2007. Bikos V et al. Leukemia 2012 Kalpadakis etal AnticancerRes2009 Dreyling M, Thieblemont, C. ESMO guidelines 2013

Splenic MZL : associated with Hepatitis C virus

Treatment IFN ou IFN + ribavarin

Disappearance of lymphocytosis and splenomegaly

E2E1

B-cell of Marginal Zone

CD81

+ MALT lymphoma+ Nodal MZL

O. Hermine et al. NEJM 2002

Clinical presentation

Most of the patients

• Asymptomatic

• Abnormal blood cells count

° Lymphocytosis

° Cytopenia (autoimmune or by hypersplenism)

• No B symptoms

• Good performance status (PS <2) : 85%

• Median age : 65

• Clinical examen : SPLENOMEGALY

C. Thieblemont et al. , 2003 – K Viala et al., 2008 – Troussard X et al., 1996 – J Chacon et al. 2002 – N Parry-Jones et al., 2003

Associated with Immune disorders

M component (IgM) 46%Marked hyperviscosity and hyperglobulinemia = uncommon

Immune disorders 20%

- Hemolytic anemia 10%

- Positive Coombs test 16%

- Thrombocytopenia 5%

- Coagulation (VW, Cardio lupic) 3%

- cold agglutinin

- Angioedema: acquired deficit in C1-esterase inhibitor

- Neuropathy (radiculopathy, axonal, demyelinating)

C. Thieblemont et al. , 2003 – K Viala et al., 2008 – Troussard X et al., 1996 – J Chacon et al. 2002 – N Parry-Jones et al., 2003

Therapeutic options

Splenectomy

Chemotherapy

Rituximab alone

Combined R-Chemotherapy

• Improvement in PS

• Correction of cytopenia

Benefit of the splenectomy

Chacon et al. Blood 2002 Thieblemont et al, Lancet Oncol 2003

• Decrease of bone marrow infiltration

Associated with a decrease of lymphocytosis

Chemotherapy

After splenectomy: benefit not established

If high LDH level and/or presence of B symptoms?

No impact on the risk of relapse, survival

If contra-indication to surgery or later in the disease

Alkylating agents (clb, cyclophosphamide)

Purine analogs (fludarabine)

Rituximab

Multidrug combination if

High LDH level or >20% Large cells

Comparative outcomes of rituximab-based systemic

therapy and splenectomy in splenic MZL

Olszewski AJ et al. Am J Hematol 2014

Prognostic factors

Overall survival

OSp

Beta2 microglobulin <3 vs 3 mg/l <0.5

Leukocytes <20 109/L vs 20 109/L <0.5

Lymphocytosis <9 109/L vs 9 109/L <0.001

Monoclonal component absent vs present 0.001

Immunological Event absent vs present NS

IPI NS

C. Thieblemont 2002

OSp

Hemoglobin 12g/dl 0.05

LDH 0.008

Albumin <0.001

L. Arcaini 2006

83%5yr OS

72%

56%PFS ?

Nodal Marginal Zone Lymphoma

Definition

Primary nodal B-cell lymphoma that sharesmorphologic, immunophenotypic, and geneticcharacteristics with extranodal MZL and splenic MZL, but without those specific localizations at presentation

1986 : « nodal monocytoid B-cell lymphoma »

1987 : « parafollicular B-cell lymphoma »

1988 : relationship established with marginal zone

1990 : included in the revised kiel classification

2001 : REAL classification

2008 : WHO classification

Sheibani et al. Am J Pathol 1986 - Cousar et al. Am J Clin Pathol - 1987 Piris M et al. Histopathology. 1988 Lennert K, Feller AC. Berlin: Springer Verlag; 1990 – Jaffe E. et al. REAL classification 1990 -Swerdlow et al WHO classification

Morphology

Heterogeneous

Infiltration : marginal zone / perifollicular, or interfollicular, perisinusoidal, follicular via colonization of reactives follicules or diffuse

Cell : several types of cells : small cells, small cells with a plasmocytoid differentiation, plasma cells, variable content of medium to large cells, monocytoid B-cell

Proportion of large cell is usually high and mitotic index is high

Is NZML a low grade lymphoma?

No correlation between number of large cell and outcome

Traverse-Glehen et al. Oncology 2012

Cytogenetic / Molecular features

No characteristic cytogenetic profil for NMZL

Recurrent clonal abnormalities : +3, +19, +7, +12, del 6q

No translocation characteristic of MALT L.

CGH : del6q23, del13q14, +3q13-q28, +6p, and + 18q

inactivation of A20

NK-KB

Biaised usage : VH4-34

Gene Sequencing : Mutation of MYD88 : 0% (/LPL)

Dierlamm J, et al. Blood.1996 - Slovak ML, et al Hum Pathol. 1993 - Callet-Bauchu E, et al. Leukemia. 2005Rinaldi A, et al. Blood. 2011 - Novak U, et al. Br J Haematol. 2011 - Novak U, et al Blood. 2009- Gachard N, et al 2013

Clinical features

Median age : 50-62 years

Disseminated nodal involvement (peripheral and visceral)

Bone marrow 28% - 44%

M-component unfrequent < 10%

Rare cytopenia

Nathwani et al Semin Diag 1999 – Armitage J Clin Oncol, 1998 – Berger et al. Blood 2000 –

Camacho et al. Am J Surg Pathol 2003 – Arcaini Cancer 2004 - Traverse-Glehen et al.

Histopathology 2006 – Petit et al. Haematoligica 2005 – Oh et al. Ann Hematol 2006 – Kojima

Cancer Sci 2007 – Gachard N et al. Leukemia 2013

A more aggressive diseasebut a good outcome

Thieblemont, C. 2005

Time to progressionOverall survival

CHLS data

Treatment

No standardized treatment

Similarly treated as FL

Rare localized cases: Radiation Therapy

Stage II to IV

- R – Anthracyclin based-regimen (CHOP, CHOP like)

- R - Bendamustine

Relapsed setting, high risk (large cells?), in eligible patients

- Intensive chemotherapy plus ASCT

Dreyling M, Thieblemont, C. ESMO guidelines 2013 – Rummel Lancet 2013

Key points for the clinician in MZL

The diagnosis may be difficult :

- borderline cases

- no diagnostic marker

Unique physiopathology : chronicantigenic stimulation

The treatment in first line is not standardized, besides HP+gastricMALT

Not curable disease but indolent diseasewith a long survival